Mycobacterium tuberculosis (M. tb) latently infects almost one third of the global population and is the primary pathogen that causes tuberculosis (TB).1 Historically, drugs are available to treat TB, but medication is taken over extended periods and drug-resistant strains are prevalent. Therefore, it is imperative to find new drugs that hit different targets essential to the survival of M. tb.
The proteins of the electron transport chain (ETC) are an excellent drug target with different mechanisms of action to those targeted by standard antimicrobials. Bedaquiline (BDQ), which inhibits the M. tb F1F0 ATP synthase, is the first-in-class drug used clinically targeting the TB ETC.2,3 However, drug resistance is still an issue.4 The cytochrome bcc (Cyt bcc) complex and cytochrome bd (Cyt bd) oxidase in the M. tb ETC have been proposed as new drug targets to combat drug resistant TB,5 and is an area of active research in our team.6
This presentation will discuss the design and synthesis of Cyt bd inhibitors using the natural product Aurachin D as a lead, with the goal to improve the selectivity of the inhibitors for M. tb over mammalian mitochondrial proteins. Key aspects of the Aurachin D scaffold were identified as important and this led to inhibitors of Cyt bd with nanomolar (nM) potency. Prodrugs of Aurachin D and other analogues were prepared as stimuli-responsive prodrugs, enabling a more targeted and potentially less toxic pathway to treating TB.